Cancer-induced cachexia (cancer cachexia) is a wasting syndrome featuring progressive loss of muscle mass (muscle wasting) due largely to excessive proteolysis. Afflicting ~50% of all cancer patients, cancer cachexia is the immediate cause of ~1/3 of all cancer-related deaths. However, there is no FDA-approved treatment for cancer cachexia due to the poor understanding of its etiology. A hallmark of cancer cachexia is the dramatic loss of myofibrillar proteins. The ubiquitin-proteasome pathway plays a major role in the loss of myofibrillar proteins in various forms of muscle atrophy by targeting myofibrillar proteins for degradation via specific E3 ubiquitin ligases. Currently, cancer-induced muscle wasting is widely thought to share common intracellular mechanisms with other types of muscle atrophy. For example, elevated E3 ligase MuRF1 is considered central for ALL forms of muscle atrophy including cancer cachexia. In addition, the Akt-FoxO1/3 signaling pathway is thought critical for ALL forms of muscle atrophy because it regulates MuRF1 expression. However, recent data revealed that cancer-induced muscle wasting appears to involve unique intracellular mechanisms distinct from muscle atrophy induced by physiological stress such as fasting, disuse or denervation. Emerging evidence suggests that MuRF1 upregulation and the Akt-FoxO1/3 signaling pathway are non-essential for cancer-induced muscle wasting in animal models as well as human patients. Instead, we found that an inflammation-activated signaling pathway involving p38 MAPK activation of transcription factor C/EBP is responsible for the bulk of muscle protein degradation in a mouse cancer cachexia model. In contrast, MuRF1 and FoxO1/3 are not responsible for the muscle wasting in this model. Further, we found that C/EBP upregulates a previously overlooked E3, UBR2, in response to a tumor burden. UBR2 is a member of an E3 ligase family that serves as the substrate recognition components of the N-end rule pathway that accounts for a large portion of total protein ubiquitylation and ATP-dependent degradation of muscle proteins induced by various catabolic stimuli. Within this E3 family, UBR2 is uniquely upregulated in the muscle of tumor-bearing rodents. Thus, we propose to test the hypothesis that UBR2 is a key E3 responsible for the excessive loss of myofibrillar proteins in cancer cachexia, and by elucidating detailed signaling mechanisms that mediate UBR2 upregulation in cancer cachexia we can ameliorate muscle wasting by targeting the signaling mechanisms using existing pharmacological inhibitors through pursuing three aims. Aim 1. To determine whether UBR2 is a key E3 ubiquitin ligase responsible for cancer-induced muscle wasting and identify its substrates. Aim 2. To determine whether site-specific acetylation of C/EBP mediates cancer-induced UBR2 upregulation. Aim 3. To determine the signaling mechanism that mediates cancer-induced acetylation of C/EBP.